PROJECT SUMMARY/ABSTRACT The goal of MODEL-AD is to generate animal models of AD that recapitulate the sporadic form of the disease. We are accomplishing this by humanizing disease relevant genetic loci ? notably the Ab sequence in APP, the Tau gene, and appropriate AD-risk variants identified via GWAS. By design, we predict the pathologies will manifest in an age-dependent fashion. C57BL/6J mice have a mean lifespan of 26.3 months for males and 24.3 months for females. Reconciling corresponding mouse and human aging timelines, C57BL/6J mice would not be expected to spontaneously develop AD-relevant pathologies until 20+ months. However, the current award only proposes phenotyping of generated mouse models up to 18 months of age. To rectify this, we now request a 3-year supplement that will enable us to age and phenotype several models to 24 months of age, where the most disease relevant pathology is expected to be found. We will introduce a screening platform to identify which MODEL-AD generated mice have the greatest potential to drive sporadic AD pathologies. The two most promising GWAS-risk-allele MODEL-AD mice identified by this screen will then be bred onto the hAb-KI/hTau mouse background and then aged to 24 months (along with the relevant control strains), and then deep phenotyped and the data released to the community. Additionally, we are evaluating mouse strains with diverse genetic backgrounds that approximate the genetic diversity in the human population, to identify which are most permissive for AD-relevant phenotypes. Through an existing supplement, both UCI and the IU/JAX groups are currently evaluating the potential of 6 independent Collaborative Cross (CC) lines to promote AD-relevant pathologies. From this we will select the 2 most permissive CC lines and introduce the human Ab sequence via CRISPR. We will then age these newly generated CC-h Ab and control parental CC lines to 24 months and perform deep phenotyping. Collectively, this supplemental award will allow us to identify and prioritize GWAS- risk allele MODEL-AD mice and genetic backgrounds that are most permissive for the development of AD- relevant pathologies, generate them with human disease relevant sequences (i.e. human Ab and/or Tau), and then age and phenotype them, leading to the generation of models of sporadic AD.